Identification of the genes reponsible for syndromes of inherited neoplasia frequently provides insight into critical pathways governing cellular growth, proliferation and signalling. Approximately 5% of primary hyperparathyroidism (HPT) is familial in nature, though many of the causative genes remain unrecognized. Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is a familial syndrome of HPT with autosomal dominant transmission and high but incomplete penetrance. The major features are HPT (90%) including 15% of all affected by HPT-JT with parathyroid cancer, jaw tumors (30%), bilateral renal cysts (10%), and less commonly solid renal tumors. Nearly 10% of adult cases appear to be silent carriers. The trait links to the HRPT2 locus at 1q25-q31. The Metabolic Diseases Branch participated in an international collaborative effort to identify the gene responsible for HPT-JT on the long arm of chromosome 1. The region on chromosome 1 was refined to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, thirteen different heterozygous, germline, inactivating mutations were identified in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations was detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a widely expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which the name parafibromin was proposed. These findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors. In previous clinical studies from our Branch we demonstrated that germline HRPT2 mutation is a rare cause of familial isolated hyperparathroidism. Current studies are focused on the expression and function of the HRPT2 gene product parafibromin.